The present study examined the prospective relationship between personality traits and the risk of polypharmacy. Participants (age range: 16-101 years; N > 15,000) were from the English Longitudinal Study of Ageing (ELSA), the Midlife in the United States Study (MIDUS), the Health and Retirement Study (HRS), the Wisconsin Longitudinal Study of Aging (WLS), and the Longitudinal Internet Studies for the Social Sciences (LISS). In each sample, personality traits and demographic factors were assessed at baseline. Number of medications was obtained from 2 to 20 years later. Random-effect meta-analyses revealed that higher neuroticism was related to a higher risk of polypharmacy (Odd Ratio = 1.30; 95% CI 1.17-1.46) and excessive polypharmacy (Odd Ratio = 1.44; 95% CI 1.18-1.77) whereas higher conscientiousness (Odd Ratio = 0.84; 95% CI 0.74-0.95) and extraversion (Odd Ratio = 0.85; 95% CI 0.73-0.98) were associated with a lower risk of polypharmacy. Openness and agreeableness were unrelated to polypharmacy. Body mass index, number of chronic conditions, and depressive symptoms partially mediated the association between personality and the number of medications. The present study provides replicable and robust evidence that neuroticism is a risk factor for simultaneous use of multiple medications, whereas conscientiousness and extraversion may play a protective role.